Human immunodeficiency viruses, HIV-1 and HIV-2, are the etiologic agents of acquired immunodeficiency syndrome (AIDS) in humans. The HIV-1 and HIV-2 envelope glycoproteins, gp120 and gp41, are critical for the entry of these viruses into the target cell, mediating virus binding to the CD4 receptor and membrane fusion. The envelope glycoproteins are the major targets for neutralizing antibodies and are likely to represent an important component in HIV-1 and/or HIV-2 vaccines. The overall goal of this proposal is to achieve an atomic level of understanding of the structural biology associated with the envelope glycoproteins of the human immunodeficiency viruses and the related simian immunodeficiency viruses. The strategy that will be employed to achieve this goal is based upon approaches that have yielded X-ray quality crystals of a complex containing an HIV-1 gp120 fragment bound to soluble fragments of CD4 and a neutralizing antibody. The structure of this complex will be determined and analyzed in Specific Aim 1. In Specific Aim 2, an attempt will be made to determine comparable structures for gp120 fragments derived from primary HIV-1 isolates in different clades. Specific Aims 3 and 4 are directed at obtaining useful crystals of HIV-1 gp120 fragments containing the complete gp41-interactive region and soluble gp120-gp41 oligomers, respectively. An attempt will be made to extend these studies to the HIV-2/SIV envelope glycoproteins in Specific Aim 5.